Clines, Clusters, and the Effect of Study Design on the Inference of Human Population Structure

Previously, we observed that without using prior information about individual sampling locations, a clustering algorithm applied to multilocus genotypes from worldwide human populations produced genetic clusters largely coincident with major geographic regions. It has been argued, however, that the degree of clustering is diminished by use of samples with greater uniformity in geographic distribution, and that the clusters we identified were a consequence of uneven sampling along genetic clines. Expanding our earlier dataset from 377 to 993 markers, we systematically examine the influence of several study design variables—sample size, number of loci, number of clusters, assumptions about correlations in allele frequencies across populations, and the geographic dispersion of the sample—on the “clusteredness” of individuals. With all other variables held constant, geographic dispersion is seen to have comparatively little effect on the degree of clustering. Examination of the relationship between genetic and geographic distance supports a view in which the clusters arise not as an artifact of the sampling scheme, but from small discontinuous jumps in genetic distance for most population pairs on opposite sides of geographic barriers, in comparison with genetic distance for pairs on the same side. Thus, analysis of the 993-locus dataset corroborates our earlier results: if enough markers are used with a sufficiently large worldwide sample, individuals can be partitioned into genetic clusters that match major geographic subdivisions of the globe, with some individuals from intermediate geographic locations having mixed membership in the clusters that correspond to neighboring regions.Synopsis: By helping to frame the ways in which human genetic variation is conceptualized, an understanding of the genetic structure of human populations can assist in inferring human evolutionary history, as well as in designing studies that search for disease-susceptibility loci. Previously, it has been observed that when individual genomes are clustered solely by genetic similarity, individuals sort into broad clusters that correspond to large geographic regions. It has also been seen that allele frequencies tend to vary continuously across geographic space. These two perspectives seem to be contradictory, but in this article the authors show that they are indeed compatible.